biostudies-literatureRozalen CWorldwide Cancer Research1549-1567.e9https://www.ebi.ac.uk/biostudies/studies/S-EPMC12416865biostudies-literatureUnknown43(8)In metastasis, the dynamics of tumor-immune interactions during micrometastasis remain unclear. Identifying the vulnerabilities of micrometastases before outbreaking into macrometastases can reveal therapeutic opportunities for metastasis. Here, we report a function of T cell immunoglobulin and mucin domain 3 (TIM3) in tumor cells during micrometastasis using breast cancer (BC) metastasis mouse models. TIM3 is highly upregulated in micrometastases, promoting survival, stemness, and immune escape. TIM3⁺ tumor cells are specifically selected during early seeding of micrometastasis. Mechanistically, TIM3 increases β-catenin/interleukin-1β (IL-1β) signaling, leading to stemness and immune-evasion by inducing immunosuppressive γδ T cells and reducing CD8 T cells during micrometastasis. Clinical data confirm increased TIM3⁺ tumor cells in BC metastasis and TIM3⁺ tumor cells as a biomarker of poor outcome in BC patients. (Neo)adjuvant TIM3 blockade reduces the metastatic seeding and incidence in preclinical models. These findings unveil a specific mechanism of micrometastasis immune-evasion and the potential use of TIM3 blockade for subclinical metastasis.Cancer cellTIM3<sup>+</sup> breast cancer cells license immune evasion during micrometastasis outbreak.PMC1241686520-0156Albanell JColl-Manzano AGuillen YAlemany AChacon JIMartinez de Duenas EBlasco-Benito STzortzi PBigas APerez-Buira SMartos TRozalen CPalomeque JAAvalle SBrunel HSangrador IComerma LBermejo BRojo FCelia-Terrassa TTorren-Duran PDalmau MGuerrero-Zotano APerez-Nunez ISanz-Flores MServitja SCasanova-Acebes MfalseTIM3<sup>+</sup> breast cancer cells license immune evasion during micrometastasis outbreak.In metastasis, the dynamics of tumor-immune interactions during micrometastasis remain unclear. Identifying the vulnerabilities of micrometastases before outbreaking into macrometastases can reveal therapeutic opportunities for metastasis. Here, we report a function of T cell immunoglobulin and mucin domain 3 (TIM3) in tumor cells during micrometastasis using breast cancer (BC) metastasis mouse models. TIM3 is highly upregulated in micrometastases, promoting survival, stemness, and immune escape. TIM3⁺ tumor cells are specifically selected during early seeding of micrometastasis. Mechanistically, TIM3 increases β-catenin/interleukin-1β (IL-1β) signaling, leading to stemness and immune-evasion by inducing immunosuppressive γδ T cells and reducing CD8 T cells during micrometastasis. Clinical data confirm increased TIM3⁺ tumor cells in BC metastasis and TIM3⁺ tumor cells as a biomarker of poor outcome in BC patients. (Neo)adjuvant TIM3 blockade reduces the metastatic seeding and incidence in preclinical models. These findings unveil a specific mechanism of micrometastasis immune-evasion and the potential use of TIM3 blockade for subclinical metastasis.2025-01-01T00:00:00Z2025 Aug2026-06-02T02:44:57.572Z2026-04-13T03:12:53.466ZS-EPMC124168654064518710.1016/j.ccell.2025.06.015